Recent advances in genome research have revealed that over one-third of open reading frames in yeast (S. cerevisiae) are predicted to be integral membrane proteins with one to fourteen transmembrane segments, reflecting the importance of membrane proteins in the life cycle of this unicellular eukaryotic organism. In multicellular organisms, cellular communication and interaction require increased biological complexity and likely an increased fraction of membrane proteins. Membrane proteins provide vital cellular functions involved in cell- cell communication, recognition, adhesion, and membrane fusion, and also in material exchange, transport and in processes of cellular energy conservation. Structural studies on a limited number of membrane proteins have contributed to our understanding of the function of these biological macromolecules. In the light of the increased number of membrane proteins being studied, the paucity of atomic structural data on membrane proteins creates a vacuum in our knowledge which is being filled rather slowly. To date, only a few families of membrane protein structures have been determined; most of them are involved in photosynthesis and respiration. The situation arises mainly due to tremendous difficulties or the near impossibility of purifying a sufficient quantity of most membrane proteins needed for structural analysis and in producing diffraction quality crystals. We, in collaboration with both intramural and extramural laboratories, explore the structure and function relations of polytopic membrane proteins crystallographically by examining a few carefully selected membrane proteins such as those involved in cellular multidrug resistance (human P-glycoprotein) and respiration (cytochrome bc1complex). We hope that these studies will result in a deep understanding of membrane protein architecture in general, the mechanism of function of these important biological membrane proteins, and in development of therapeutics. - membrane protein complexes, Biochemistry, Cancer, computational biology, computer modeling, Drug Discovery, Drug resistance, drug transport, membrane proteins, molecular structure, Oxidation/reduction, protein structure, protein-protein interaction, proteolysis, - Neither Human Subjects nor Human Tissues